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WO2021193951A1 - Composé de sucre ayant une chaîne de polyéthylène glycol, et précurseur de complexe anticorps-médicament - Google Patents

Composé de sucre ayant une chaîne de polyéthylène glycol, et précurseur de complexe anticorps-médicament Download PDF

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WO2021193951A1
WO2021193951A1 PCT/JP2021/012997 JP2021012997W WO2021193951A1 WO 2021193951 A1 WO2021193951 A1 WO 2021193951A1 JP 2021012997 W JP2021012997 W JP 2021012997W WO 2021193951 A1 WO2021193951 A1 WO 2021193951A1
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Inventor
後藤　浩太朗
水野　真盛
昭生 松田
亘 月村
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Noguchi Institute
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Noguchi Institute
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Priority to US17/907,119 priority Critical patent/US20230218766A1/en
Priority to JP2022510760A priority patent/JP7144643B2/ja
Priority to EP21776082.6A priority patent/EP4130016A4/fr
Publication of WO2021193951A1 publication Critical patent/WO2021193951A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • A—HUMAN NECESSITIES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C07H15/08—Polyoxyalkylene derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification

Definitions

  • the present invention is a modified immunoglobulin antibody that is a precursor of an antibody-drug conjugate (ADC), and a sugar compound having a polyethylene glycol chain modified with a functional group as a raw material for its synthesis. (Sugar oxazoline compound).
  • ADC has been attracting attention as a next-generation antibody drug in which a drug having cytotoxic activity is bound to an antibody drug that specifically binds to a target antigen expressed in cancer cells.
  • ADC for example, a method of binding a drug to a side chain amino group or thiol group of an IgG antibody via a linker is generally used, and amino groups existing at a plurality of locations on the antibody are generally used. Since it is randomly introduced into the or thiol group, a diverse group of ADC isomers having a wide distribution in the position and number of drug introductions can be obtained. Such ADC isomers are concerned about clinical problems such as quality control and drug efficacy (decreased circulation half-life and efficacy).
  • Non-Patent Documents 1 and 2 a method for regioselectively introducing a drug using an N-linked sugar chain in the Fc region of an IgG antibody as a foothold has been reported (Non-Patent Documents 1 and 2). Since these methods can selectively introduce the drug only into the sugar chain portion on the antibody, they have the advantages of higher regioselectivity and controllable number of drug introductions than the conventional random drug introduction method. have.
  • N-acetylneuraminic acid may be released from sugar chains in blood, and there is a concern that the drug may be released from the ADC outside the target cells.
  • sugar chains used in these methods are prepared from chicken eggs, egg-derived allergens pose a problem from the viewpoint of GMP in drug production.
  • An object of the present invention is to provide a method for synthesizing ADCs that can regioselectively control the number of drugs introduced, and synthetic intermediates and synthetic raw materials for that purpose.
  • glycoxazoline derivative that is a tool for ADC synthesis that can regioselectively control the number of introduced drugs for antibodies. Since the glycooxazoline derivative of the present invention is a completely chemically synthesized product, it is suitable for mass synthesis and can overcome the problem of allergens. Furthermore, since it does not have N-acetylneuraminic acid in the molecule, it is expected that the problem of blood stability can be overcome. In addition, this sugar oxazoline derivative can be regioselectively introduced into the sugar site of the antibody by using endo- ⁇ -N-acetylglucosaminidase (ENGase), which is one of the sugar hydrolases.
  • ENGase endo- ⁇ -N-acetylglucosaminidase
  • X is independently a single bond, an oxygen atom, -NH-, -COHN-, -COO-, or formula (5) or (6):
  • R 1 is a trivalent branched hydrocarbon group having 1 to 6 carbon atoms, and R 2 and R 3 are independently alkylene groups having 1 to 3 carbon atoms). It is a group, and any one or more of Y1 to 3 are present, and each independently has a PEG chain, a substituted PEG chain, or an oxygen atom, -NH-, -COHN-, or -COO- as the main chain.
  • the PEG chain contained in the above, the structure of the PEG chain is a linear structure or a branched structure, and in the case of a branched structure, the number of branches is 2 to 10, and Z is independently a hydroxy group, a methoxy group, and an azide.
  • X is a group represented by the above formula (5) or (6)
  • Y1 to 3 are bonded to R 2 and R 3 of the branched chain, respectively, and when the PEG chain has a branched structure, the respective branches are formed.
  • Z is attached to the chain.
  • the sugar compound having a polyethylene glycol chain according to [1] which is represented by the following general formula (2). (In equation (2), l and n each independently represent an integer from 2 to 10.)
  • Compound 12 the following formula: The sugar compound having a polyethylene glycol chain according to [1], which is selected from the group consisting of the compound represented by, compound 66, compound 72, compound 78, compound 83, and compound 94.
  • a sugar compound group having a polyethylene glycol chain represented by (in the formula, X, Y1 to 3, and Z are as described above, and R is an L-fucose or a hydrogen atom) is used as an asparagine residue in the Fc region.
  • Modified immunoglobulin antibody at the sugar binding site of the side chain of [5] The immunoglobulin antibody is an immunoglobulin G antibody, and the asparagine residue in the Fc region is the 297th asparagine residue in the Fc region, which is represented by the following general formula (3), in [4].
  • modified immunoglobulin antibody In the formula, in the formula, X, Y1 to 3, and Z are as described above, R is L-fucose or a hydrogen atom), and [6] the sugar compound having the polyethylene glycol chain is [2. ], which is the modified immunoglobulin antibody according to [5] represented by the following general formula (4).
  • R represents L-fucose or hydrogen.
  • L and n represent integers from 2 to 10.
  • the present specification discloses sugar oxazoline derivatives as follows and modified IgG antibodies that serve as ADC precursors derived from them.
  • a sugar oxazoline derivative to which a polyethylene glycol (PEG) chain having a functional group is bonded which is represented by the following general formula (1).
  • X represents an oxygen or an amide group.
  • Y1 to 3 always have at least one of them, and represent a PEG chain or a PEG derivative derivatized with a functional group and / or an organic group.
  • the structure of the PEG chain and the PEG derivative is a linear structure or a branched structure, and in the case of the branched structure, the number of branches is 2 to 10, Z indicates an azide group or a tetrazine derivative. At the location, Z indicates hydrogen and X indicates oxygen.
  • the number of l, m, and n is 1 when Y1 to 3 have a linear structure, and is equal to or less than the number of branches when Y1 to 3 have a branched structure, and Y1 to Y1 to 3.
  • the number of l, m, and n is 1 in the place where any of 3 does not exist.
  • Z is not the same even if it is the same.
  • the bond between XY and YY is a covalent bond, and X, Y and Z do not have to be the same at each display.
  • Modified IgG which is an ADC precursor represented by the following general formula (3) obtained by reacting IgG with a glycooxazoline derivative represented by the general formula (1) in the presence of ENGase.
  • a glycooxazoline derivative represented by the general formula (1) in the presence of ENGase.
  • an unprecedented ADC precursor capable of introducing a fixed number of drugs at a specific position on an antibody, having a chemically and biochemically stable structure, and overcoming allergen problems.
  • a modified antibody can be prepared.
  • the sugar compound of the present invention for binding an antibody to a drug, the drug can be introduced into the antibody-drug conjugate under mild conditions (pH, temperature, etc.). Therefore, the antibody is not deteriorated during the reaction.
  • FIG. 5 shows a one-pot rearrangement reaction of Compound 12 to native trastuzumab in the reaction of Example 14.
  • sugar compound of the present invention is a sugar oxazoline derivative and is represented by the following general formula (1).
  • X is independently a single bond, an oxygen atom, -NH-, -COHN-, -COO-, or formula (5) or (6):
  • R 1 is a trivalent branched hydrocarbon group having 1 to 6 carbon atoms
  • R 2 and R 3 are independently alkylene groups having 1 to 3 carbon atoms).
  • Y1 to 3 are present, and each independently contains a PEG chain, a substituted PEG chain, or an oxygen atom, -NH-, -COHN-, or -COO- in the main chain.
  • the structure of the PEG chain is a linear structure or a branched structure, and in the case of the branched structure, the number of branches is 2 to 10.
  • Z is independently a hydroxy group, a methoxy group, an azide group, a tetrazine group which may be substituted, a norbornene group, a trans-cyclooctene group, a dibenzylcyclooctyl group, or a bicyclo [6.1.0.
  • X binds a sugar to a PEG chain or the like, and independently of each of them is a single bond, an oxygen atom, -NH-, -COHN-, -COO-, or formula (5) or (6) :.
  • R 1 is a trivalent branched hydrocarbon group having 1 to 6 carbon atoms
  • R 2 and R 3 are independently alkylene groups having 1 to 3 carbon atoms. Is the basis.
  • X is a single bond, an oxygen atom, -NH-, -COHN-, or -COO-, there is only one PEG chain or the like bonded to X.
  • X is a group represented by the formula (5) or (6), a PEG chain or the like is bonded to each branch.
  • Y1 to Y3 may be a PEG chain, a substituted PEG chain, or a PEG chain containing an oxygen atom, -NH-, -COHN-, or -COO- as a main chain (hereinafter, collectively referred to as a PEG chain or the like).
  • the structure such as the PEG chain may be a linear structure or a branched structure.
  • PEG chains and the like are non-toxic and non-immunogenic macromolecules, and protein therapeutic agents modified with PEG chains and the like are raw due to decreased immunogenicity, protection from degradation by various enzymes, and increased half-life. The effect of increasing stability in the body can be obtained.
  • the number of repetitions of the PEG chain is not particularly limited, but is, for example, 2 to 1000, 2 to 100 in some embodiments, 2 to 50 in some embodiments, and 2 to 50 in some embodiments. It is 30, in some embodiments 2 to 20, in some embodiments 2 to 10, and in some embodiments 2 to 5.
  • the number of repetitions is the number of repetitions in one PEG chain, and in the case of a branched PEG chain, it means the number of repetitions in each branched PEG chain.
  • the number of repetitions in a PEG chain containing an oxygen atom, -NH-, -COHN-, or -COO- described later in the main chain means the number of repetitions in one PEG chain containing these groups.
  • the substituted PEG chain means a PEG chain in which a hydrogen atom in the side chain of the PEG chain is substituted.
  • the substituent is not particularly limited as long as the effect of the present invention can be obtained, but an alkyl group, an aralkyl group, an alkenyl group, an alkynyl group, a hydroxyl group, an amino group, an aldehyde group, a ketone group, a carboxyl group, etc. Examples thereof include an amide group, a thiol group, and an ether group, and an alkyl group having 1 to 6 carbon atoms is particularly preferable.
  • the PEG chain containing the oxygen atom, -NH-, -COHN-, or -COO- in the main chain is the oxygen atom (ether bond) between the repeating units of polyethylene glycol (CH 2 CH 2 O) in the main chain. ), -NH-, -COHN- (amide bond), or -COO- (ester bond).
  • the main chain polyethylene glycol (CH 2 CH 2 O) may be replaced with an oxygen atom (-O-) to contain -NH-, -COHN-, or -COO-.
  • the PEG chain or the like has a linear structure or a branched structure.
  • the number of branches is not limited, but 2 to 10 is preferable.
  • the degree of polymerization of the PEG chain is also not particularly limited as described above, but the degree of polymerization 2 to 10 is particularly preferable.
  • Z is a hydroxy group, a methoxy group, an azido group, a tetrazine group, a norbornene group, a trans-cyclooctene group, or a dibenzylcyclooctene, which may be substituted in the place where Y1 to 3 are present.
  • any of Y1 to Y3 is absent, hydrogen is indicated, and X is oxygen.
  • at least one or more Z is not a hydroxy group or a methoxy group.
  • At least one Z is an azide group, optionally a tetrazine group, a norbornen group, a trans-cyclooctene group, a dibenzylcyclooctene group, or a bicyclo [6.1.0] nona-4-.
  • At least one Z is an azide group, an optionally substituted tetrazine group, a norbornen group, a trans-cyclooctene group, a dibenzylcyclooctene group, or a bicyclo [6.1.0] nona-4-in-.
  • the drug can be efficiently introduced into the sugar compound of the present invention.
  • the azide group a group represented by -N 3.
  • the tetrazine group is a 1,2,4,5-tetrazine group.
  • the substituent of the substituted tetrazine group is one in which the hydrogen atom at the 3-position and / or the 6-position is substituted.
  • the substituent at the 3-position is not limited, but is limited to an alkyl group having 1 to 3 carbon atoms, a pyridinyl group, a bipyridinyl group, 3 CF groups (fluoroalkyl group), -COOCH 3 (ester group), or Examples include phenyl groups.
  • the substituent at the 6-position includes, but is not limited to, an amino group, an alkylene group having 1 to 3 carbon atoms (for example, an ethylene group), a phenylene group, or a pyridinylene group. Further, an amino group as a substituent at the 6-position, an alkylene group having 1 to 3 carbon atoms (for example, an ethylene group), a phenylene group, or a pyridinylene group is bonded to Y1 to 3 via an amide bond or an amino group. You may.
  • the tetrazine group or the substituted tetrazine group may be directly bonded to the PEG chain or the like, or may be bonded by, for example, an ether bond, an ester bond, a carbonate bond, a carbamate bond, an amide bond or the like.
  • Specific examples of the substituted tetrazine group include, but are not limited to, a group represented by the following formula.
  • the norbornene group has the following formula (8): It is a group represented by.
  • the norbornene group may be directly bonded to the PEG chain or the like, or may be bonded by, for example, an ether bond, an ester bond, a carbonate bond, a carbamate bond, an amide bond or the like.
  • the trans-cyclooctene group has the following formula (9): It is a group represented by.
  • the trans-cyclooctene group may be directly bonded to the PEG chain or the like, or may be bonded by, for example, an ether bond, an ester bond, a carbonate bond, a carbamate bond, or an amide bond.
  • the dibenzylcyclooctyl group has the following formula (10): It is a group represented by.
  • the dibenzylcyclooctyl group may be directly bonded to the PEG chain or the like, or may be bonded by, for example, an ether bond, an ester bond, a carbonate bond, a carbamate bond, an amide bond or the like.
  • the bicyclo [6.1.0] nona-4-in-9-ylmethyl group has the following formula (11): It is a group represented by.
  • the bicyclo [6.1.0] nona-4-in-9-ylmethyl group may be directly bonded to the PEG chain or the like, and may be, for example, an ether bond, an ester bond, a carbonate bond, a carbamate bond, or an amide bond. It may be combined by such as.
  • the cyanobenzothiazole group has the following formula (12): It is a group represented by.
  • the substituted cyanobenzothiazole group is one in which the bond with Y1 to 3 is bonded via an amide bond, an ether bond, or an ester bond.
  • the cyanobenzothiazole group and the substituted cyanobenzothiazole group may be directly bonded to the PEG chain or the like, or may be bonded by, for example, an ether bond, an ester bond, or an amide bond.
  • Z may or may not be the same.
  • the substituent in Y1 to 3 of the general formula (1) is not particularly limited, and examples thereof include an organic group and a functional group.
  • the organic group is an aggregate of atoms that require a carbon atom, and examples thereof include an alkyl group, an aralkyl group, an alkenyl group, and an alkynyl group, and an alkyl group and an alkenyl group are particularly preferable.
  • the structure of the alkyl group and the alkenyl group is not particularly limited, and may be a saturated or unsaturated chain hydrocarbon group or an alicyclic hydrocarbon group.
  • the number of carbon atoms of the alkyl group and the alkenyl group is not particularly limited, but 1 to 30 is preferable, and 1 to 20 is particularly preferable.
  • a functional group is an aggregate of atoms that determines the properties of an organic compound, and examples thereof include a hydroxyl group, an amino group, an aldehyde group, a ketone group, a carboxyl group, an amide group, a thiol group, and an ether group, and in particular, a hydroxyl group and an amino group.
  • a group, a carboxyl group, an amide group and an ether group are preferable.
  • sugar compound (sugar oxazoline derivative) of the present invention a sugar compound (oxazoline derivative) represented by the following formula (2) is preferable.
  • the degree of polymerization of the polyethylene glycol chain is not particularly limited, but the degree of polymerization is preferably 2 to 10.
  • sugar compound (sugar oxazoline derivative) of the present invention include a sugar compound (oxazoline derivative) represented by the following formula.
  • the modified immunoglobulin antibody of the present invention is derived from the sugar compound having a polyethylene glycol chain according to the following formula (7): (In the formula, X, Y1 to 3, and Z are as described above, and R is L-fucose or a hydrogen atom.) A sugar compound group having a polyethylene glycol chain represented by an asparagine residue in the Fc region. It is present at the sugar binding site of the side chain of. By reacting an antibody with a sugar compound (sugar oxazoline derivative) represented by the general formula (1) in the presence of ENGase, a modified immunoglobulin antibody having a sugar compound group represented by the formula (7) can be obtained.
  • the antibody is not particularly limited, and examples thereof include IgG, IgA1, IgA2, IgE, IgD, and IgM.
  • the asparagine residue in the Fc region of IgG is at position 297.
  • Asparagine residues in the Fc region of IgA1 are at positions 144 and 340.
  • Asparagine residues in the Fc region of IgA2 are at positions 131, 205, and 327.
  • Asparagine residues in the Fc region of IgE are at positions 140, 168, 218, 265, 371, 383, and 394.
  • Asparagine residues in the Fc region of IgD are at positions 354, 445, and 496.
  • Asparagine residues in the IgMFc region are at positions 171, 332, 395, 402, and 563.
  • a modified IgG antibody which is an ADC precursor represented by the following general formula (3) can be obtained.
  • X, Y1 to 3, and Z are as described above, and R is L-fucose or a hydrogen atom.
  • the modified IgG antibody represented by the following general formula (4) is particularly preferable as the product of the present invention.
  • R represents L-fucose or hydrogen.
  • L and n represent integers from 2 to 10.
  • the antibody-drug conjugate of the present invention controls the release rate, release mechanism, and release location of a drug in Z of the sugar compound, for example, a linker (a molecule that links an antibody and a drug. It binds via a molecule) and binds the asparagine residue of the antibody to the oxazoline skeleton of the sugar compound.
  • a linker a molecule that links an antibody and a drug. It binds via a molecule
  • the linker include, but are not limited to, Val-Cit linker, MCC linker, and Gly-Gly-Phe-Gly linker.
  • the sugar compound (sugar oxazoline derivative) of the present invention is reacted with the antibody in the presence of ENGase to introduce the sugar compound (sugar oxazoline derivative) of the present invention into aspartic acid in the Fc portion of the antibody.
  • the modified immunoglobulin antibody of the present invention binds a drug to the Z group.
  • the Z group (azide group, derivative of tetrazine group, norbornene group, trans-cyclooctene group, dibenzylcyclooctene group, or bicyclo [6.1.0] nona-4-in-9-ylmethyl group, or cyano
  • the benzothiazole group derivative can introduce the drug under mild conditions. For example, the reaction can proceed rapidly at room temperature at a pH in the neutral range. Therefore, the antibody is not exposed to a high temperature and the deterioration of the antibody does not occur.
  • a sugar compound having a PEG chain having an azide group at the terminal was prepared.
  • Compound 1 (2.03 g, 8.52 mmol) was dissolved in toluene (40 mL), p-methoxybenzyl chloride (1.27 mL, 9.37 mmol), potassium iodide (283 mg, silver (I) oxide (2.96 g)). , 12.8 mmol) were sequentially added, and the mixture was stirred overnight at 60 ° C. The solid matter was filtered off, washed with chloroform, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography.
  • Example 2 the compound obtained in Example 1 was bound to rituximab (antibody).
  • the acceptor (13) of rituximab was prepared according to Non-Patent Document 4 using rituximab manufactured by Zenyaku Kogyo Co., Ltd.
  • the transfer reaction of compound 12 to the sugar chain binding site of rituximab acceptor 13 was performed with the prepared rituximab acceptor 13 (2 mg), compound 12 (1.384 ⁇ mol), and the wild-type enzyme Endo-F3 expressed and purified in Escherichia coli.
  • Example 3 a fluorescent group was introduced into the azide group.
  • the aqueous solution (7.0 ⁇ g / ⁇ L) of the reaction product obtained in Example 2 was added to 4.0 ⁇ L, 2.0 ⁇ L of 1.0 M pH 8.0 phosphate buffer, 15.3 ⁇ L of water, and 1% DMSO of compound 16. 18.7 ⁇ L of an aqueous solution (100 ⁇ M) was added, and the mixture was reacted at room temperature for 2 hours in the dark.
  • Example 4 a sugar compound having a PEG chain having a tetrazine group at the terminal was prepared.
  • Commercially available compound 17 (5.01 g, 11.2 mmol) was dissolved in dichloromethane (6 mL), a 25% hydrogen bromide acetic acid solution (15 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. Ice water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic phase was washed with water (twice), saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and then dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.
  • the obtained compound 34 can be induced into an oxazoline form by using an existing oxazoline formation method.
  • Example 6 the drug was introduced into the azide group of compound 12.
  • Triethylamine (16.1 ⁇ L, 116 ⁇ m Cincinnatil) and a 100 mM DMSO solution of compound 48 (462 ⁇ L, 46.2 ⁇ m Reasonl) were sequentially added to a 100 mM DMSO solution (358 ⁇ L, 38.5 ⁇ m Cincinnatil) of compound 47, and the mixture was stirred at room temperature for 4 hours.
  • Example 7 a sugar compound having a PEG chain having a tetrazine group substituted at the terminal was prepared.
  • Compound 53 Compound 52 (2.46 g, 2.36 mmol) with 1.0 MBH 3 THF solution (17.7 mL, 17.7 mmol) and 1.0 Mn-Bu 2 BOTf dichloromethane solution (3.35 mL, 3.35 mmol) in sequence.
  • the mixture was stirred at 0 ° C. for 1 hour under an argon atmosphere.
  • the obtained residue was dissolved in DMF (7 mL), sodium azide (233 mg, 3.60 m mmol) was added, and the mixture was stirred at 65 ° C. for 18 hours.
  • the reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.
  • Example 8 a branched sugar compound having a PEG chain having an azide group and a substituted tetrazine group at the end was prepared.
  • Example 9 a sugar compound having a PEG chain having an azide group at the terminal was prepared.
  • Compound 73 (55.9 mg, 192 ⁇ mol) was dissolved in dichloromethane (2 mL) and N-hydroxysuccinimide (39.0 mg, 339 ⁇ mol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (64.7 mg). , 338 ⁇ mol) were added sequentially, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform.
  • Example 10 a branched sugar compound having a PEG chain having an azide group at the terminal was prepared.
  • L-lysine methyl ester dihydrochloride 108 mg, 462 ⁇ mol
  • dichloromethane 1.6 mL
  • compound 67 305 mg, 1.23 mmol
  • N, N-diisopropylethylamine (0.45 mL, 3.2 mmol)
  • 1- [bis (dimethylamino) methylene] -1H-benzotriazolium 3-oxide tetrafluoroborate (390 mg,) in this solution under ice-cooling.
  • Example 11 a sugar compound having three azide groups at the end was prepared.
  • Compound 84 Compound 35 (797.4 mg, 852 ⁇ mol) was dissolved in methanol (6.80 mL) and ethylenediamine (1.70 mL) was added at room temperature. The reaction mixture was stirred under heating under reflux for 17 hours, the reaction mixture was diluted with dimethylformamide, and the solvent was evaporated under reduced pressure. The crude product was obtained by azeotropically boiling with dimethylformamide three times and vacuum drying the residue.
  • the reaction mixture was stirred at room temperature for 18 hours, and sodium hydrogen carbonate (152.3 mg, 1.81 mmol) and imidazole-1-sulfonyl azide hydrochloride (359.3 mg, 1.71 mmol) were added.
  • the reaction mixture was stirred at room temperature for 3 hours, the reaction mixture was diluted with chloroform, a 1 M aqueous hydrochloric acid solution was added, and the mixture was extracted 3 times with chloroform.
  • the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and extracted 3 times with chloroform.
  • the organic layer was dried over anhydrous magnesium sulfate, filtered off, and the solvent was evaporated under reduced pressure.
  • the crude product 87 is dissolved in dichloromethane (5.5 mL), 1,3-dimethoxybenzene (107.5 ⁇ L, 832 ⁇ mol) is added at room temperature, and trifluoromethanesulfonic acid (36.7 ⁇ L, 416 ⁇ mol) is added under ice-cooling. rice field.
  • the reaction mixture was stirred at room temperature for 1 hour, diluted with chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with chloroform.
  • the organic phase was dried over anhydrous sodium sulfate, filtered off, and the solvent was evaporated under reduced pressure. The residue was vacuum dried to give a crude product.
  • the crude product was dissolved in dichloromethane (2.77 mL) and methanol (2.77 mL), and a 28% sodium methoxide-methanol solution (50 ⁇ L) was added at room temperature.
  • the reaction mixture was stirred at room temperature for 6 hours, diluted with chloroform, neutralized by adding Amberlite IR-120 (H + form), and the resin was filtered off.
  • Example 12 drug-bound rituximab was prepared.
  • Aqueous solution (7.0 ⁇ g / ⁇ L) of the reaction product obtained in Example 2 was added to 30.0 ⁇ L to 1.0 M pH 8.0 phosphate buffer (15.0 ⁇ L), water (165 ⁇ L), DMSO (76 ⁇ L).
  • MMAE drug site monomethylolistatin E
  • Example 13 the effect of rituximab obtained in Example 12 on cytotoxicity was examined.
  • CD20-positive Ramos (RA1) cells and CD20-negative Jurkat cells were used in RPMI-1640 medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing SuperLow IgGFBS (Cytiva) and ZellShield (Minerva Biolabs) at a final concentration of 10%. Cultured and prepared. Ramos (RA1) cells or Jurkat cells suspended in the medium were seeded in a 96-well microplate (Corning) at 1.0 x 10 4 cells / 90 ⁇ L per well.
  • a blank medium-only well was also prepared. Then, the cells were cultured overnight in an incubator at 37 ° C. and 5% CO 2. The next day controls PBS, rituximab, azide PEGylated rituximab obtained in Example 2, or MMAE-loaded rituximab obtained in Example 12 were added to each well in an amount of 10 ⁇ L each, and an incubator at 37 ° C. and 5% CO 2 was added. It was allowed to stand in the room for 72 hours. The antibody sample was diluted with PBS and added to a final concentration of 50, 500 or 5000 ng / mL in the culture medium.
  • MMAE-loaded rituximab had reduced absorbance at antibody concentrations of 500 and 5000 ng / mL, confirming that the cells were killed.
  • CD20-negative Jurkat cells the absorbance was almost unchanged at each antibody concentration, and no clear cell-killing effect was observed.
  • Example 14 In this example, compound 12 was introduced into trastuzumab. (Transfer reaction of compound 12 to the trastuzumab sugar chain binding site (one-pot reaction. Another method of Example 2 that does not require prior preparation of antibody acceptor)) Trastuzumab (80 ⁇ g) manufactured by Chugai Pharmaceutical Co., Ltd., compound 12 (54 nmol), and the enzyme Halo-Endo-S wild type (8 ⁇ g) purified by expressing Escherichia coli as a host in 50 mM Tris-hydrochloric acid buffer (pH 7.0). In addition, the total volume was 20 ⁇ L, and the mixture was allowed to stand at 37 ° C. for up to 3 hours.
  • the sugar compound of the present invention can prevent the deterioration of the antibody and efficiently bind the drug to the antibody in the preparation of the antibody-drug conjugate.

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Abstract

La présente invention aborde le problème de la fourniture : d'un procédé de synthèse d'un conjugué anticorps-médicament (ADC) permettant de contrôler l'introduction sélective de molécules d'un médicament et le contrôle du nombre de molécules du médicament à introduire ; ainsi qu'un intermédiaire de synthèse et une matière première de synthèse pour le procédé.　La solution selon l'invention porte sur un composé de sucre ayant une chaîne de polyéthylène glycol, qui est représenté par la formule générale (1). (Dans la formule (1), les X' représentent indépendamment une liaison simple, un atome d'oxygène, -NH-, -COHN-, -COO- ou un groupe représenté par la formule (5) ou (6) (R1 étant un groupe hydrocarboné ramifié trivalent ayant de 1 à 6 atomes de carbone ; et R2 et R3 étant indépendamment un groupe alkylène ayant de 1 à 3 atomes de carbone) ; au moins l'un de Y1 à Y3 est présent, et Y1 à Y3 représentent indépendamment une chaîne PEG, une chaîne PEG substituée, ou une chaîne PEG contenant un atome d'oxygène, -NH-, -COHN- ou -COO- dans sa chaîne principale, la structure de chacune de la chaîne PEG étant une structure de doublure ou une structure ramifiée, et, lorsque la structure de chacune de la chaîne PEG est une structure ramifiée, le nombre de ramifications est de 2 à 10 ; les Z représentent indépendamment un groupe hydroxy, un groupe méthoxy, un groupe azide, un groupe tétrazine éventuellement substitué, un groupe norbornène, un groupe trans-cyclooctène, un groupe dibenzylcyclooctyle, un groupe bicyclo[6.1.0]non-4-yn-9-ylméthyle, ou un groupe cyanobenzothiazole éventuellement substitué, au moins l'un des Z n'étant pas un groupe hydroxy ou un groupe méthoxy ; lorsque l'un quelconque de Y1 à Y3 n'est pas présent, le Z correspondant représente un atome d'hydrogène et le X correspondant représente un atome d'oxygène ; lorsque X représente indépendamment un groupe représenté par la formule (5) ou (6), Y1 à Y3 sont respectivement liés à R2 et R3 dans la chaîne ramifiée ; et lorsque chacune des chaînes PEG a une structure ramifiée, Z est lié à chacune des chaînes ramifiées dans la structure ramifiée.)
PCT/JP2021/012997 2020-03-26 2021-03-26 Composé de sucre ayant une chaîne de polyéthylène glycol, et précurseur de complexe anticorps-médicament Ceased WO2021193951A1 (fr)

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EP21776082.6A EP4130016A4 (fr) 2020-03-26 2021-03-26 Composé de sucre ayant une chaîne de polyéthylène glycol, et précurseur de complexe anticorps-médicament

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WO2025148977A1 (fr) * 2024-01-10 2025-07-17 上海齐鲁制药研究中心有限公司 Nouveau lieur disaccharide, son procédé de préparation et son utilisation

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